K. A. Frondorf

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The potent irreversible inhibitor of S-adenosyl-L-homocysteine hydrolase (Z)-5'-fluoro-4',5'-didehydro-5'-deoxyadenosine (MDL 28,842) was examined for its effect on the development and treatment of collagen-induced arthritis in mice. We have previously shown that MDL 28,842 inhibits T cell activation without affecting B cell activation. Animals were dosed(More)
Defects in the enzymes involved in the pathway of S-adenosylmethionine (AdoMet) metabolism, or inhibition of those enzymes, results in profound immunodeficiency. We have examined MDL 28,842, a novel irreversible inhibitor of S-adenosyl-L-homocysteine hydrolase (AdoHcyase), an enzyme involved in AdoMet metabolism, to determine its effect on the immune system(More)
The response of murine T cells to MHC class II determinants on allogeneic cells induces helper T cell activation and the development of cytotoxic T cells. We have recently established that an S-adenosyl-L-homocysteine hydrolase inhibitor, (Z)-5'-fluoro-4',5'-didehydro-5'-deoxyadenosine (MDL 28,842), is a potent immunosuppressive agent which selectively(More)
The product of phospholipase D (PLD) enzymatic action in cell membranes, phosphatidic acid (PA), regulates kinases implicated in NADPH oxidase activation, as well as the mammalian target of rapamycin (mTOR) kinase. However, other protein targets for this lipid second messenger must exist in order to explain other key PA-mediated cellular functions. In this(More)
We report here that the enzymatic activity of phospholipase D2 (PLD2) is regulated by phosphorylation-dephosphorylation. Phosphatase treatment of PLD2-overexpressing cells showed a biphasic nature of changes in activity that indicated the existence of "activator" and "inhibitory" sites. We identified three kinases capable of phosphorylating PLD2 in(More)
Phosphatidic acid (PA) is a pleiotropic lipid second messenger in mammalian cells. We report here that extracellular PA acts as a leukocyte chemoattractant, as membrane-soluble dioleoyl-PA (DOPA) elicits actin polymerization and chemotaxis of human neutrophils and differentiated proleukemic HL-60 cells. We show that the mechanism for this involves the S6(More)
We report the molecular mechanisms that underlie chemotaxis of macrophages and cell migration of fibroblasts, cells that are essential during the body's innate immune response and during wound repair, respectively. Silencing of phospholipase D1 (PLD1) and PLD2 reduced cell migration (both chemokinesis and chemotaxis) by approximately 60% and >80%,(More)
Janus kinase 3 (JAK3) is a non-receptor tyrosine kinase vital to the regulation of T-cells. We report that JAK3 is a mediator of interleukin-8 (IL-8) stimulation of a different class of hematopoietic relevant cells: human neutrophils. IL-8 induced a time- and concentration-dependent activation of JAK3 activity in neutrophils and differentiated HL-60(More)
The control of ribosomal RNA (rRNA) gene expression during development can be productively studied by examination of the relationship between promoter structure and function as well as the processing of primary transcripts. Toward this end total cell RNA was extracted from embryos at various stages and probed with cloned rRNA genes using the "dot blot"(More)
The adaptor protein Grb2 associates with phospholipase D2 (PLD2), but it is not known if this interaction is necessary for the functionality of the lipase in vivo. We demonstrate that stable short hairpin RNA (shRNA)-based silencing of Grb2, a critical signal transducer of the epidermal growth factor receptor (EGFR) and linker to the Ras/Erk pathway,(More)